Breast Cancer. Key Words. Breast cancer Estrogen Estrone sulfate Steroid sulfatase Sulfatase inhibitor

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1 The Oncologist Breast Cancer Steroid Sulfatase: A New Target for the Endocrine Therapy of Breast Cancer SUSANNAH J. STANWAY, a PATRICK DELAVAULT, b ATUL PUROHIT, a L. W. LAWRENCE WOO, c CHRISTOPHE THURIEAU, b BARRY V. L. POTTER, c MICHAEL J. REED a a Endocrinology and Metabolic Medicine and Sterix Ltd., Imperial College, St. Mary s Hospital, London, United Kingdom; b Ipsen, Institute Henri Beaufour, Les Ulis, France; c Medicinal Chemistry, Department of Pharmacy and Pharmacology and Sterix Ltd., University of Bath, Bath, United Kingdom Key Words. Breast cancer Estrogen Estrone sulfate Steroid sulfatase Sulfatase inhibitor LEARNING OBJECTIVES After completing this course, the reader will be able to: 1. Discuss the role of steroid sulfatase in regulating estrogen production in postmenopausal women. 2. Describe the potential of steroid sulfatase inhibition in cancer therapy. 3. Discuss a potential new endocrine therapy for patients progressing on aromatase. CME Access and take the CME test online and receive 1 AMA PRA Category 1 Credit at CME.TheOncologist.com ABSTRACT Inhibitors of steroid sulfatase are being developed as a novel therapy for hormone-dependent breast cancer in postmenopausal women. Data suggest that steroid sulfatase (STS) activity is much higher than aromatase activity in breast tumors and high levels of STS mrna expression in tumors are associated with a poor prognosis. STS hydrolyzes steroid sulfates, such as estrone sulfate and dehydroepiandrosterone sulfate (DHEAS), to estrone and DHEA, which can be converted to steroids with potent estrogenic properties, that is, estradiol and androstenediol, respectively. Several potent irreversible STS inhibitors have now been identified, including STX64 (BN83495), a tricyclic sulfamate ester. This drug recently completed the first-ever trial of this new type of therapy in postmenopausal women with estrogen receptor positive metastatic breast cancer. STX64, tested at 5-mg and 20-mg doses, was able to almost completely block STS activity in peripheral blood lymphocytes and tumor tissues. Inhibition of STS activity was associated with significant reductions in serum concentrations of androstenediol and estrogens. Unexpectedly, serum androstenedione concentrations also decreased by up to 86%, showing that this steroid, which is the main substrate for the aromatase in postmenopausal women, is derived mainly from the peripheral conversion of DHEAS. Of eight patients who completed therapy, five showed evidence of stable disease for up to 7.0 months. This new endocrine therapy offers considerable potential for the treatment of hormone-dependent breast cancer in postmenopausal women. The Oncologist 2007;12: Disclosure of potential conflicts of interest is found at the end of this article. Correspondence: M. J. Reed, Ph.D., D.Sc., F.R.C. Path, Endocrinology and Metabolic Medicine, Imperial College, St. Mary s Hospital, London, W2 1NY, United Kingdom. Telephone: ; Fax: ; m.reed@imperial.ac.uk Received October 4, 2006; accepted for publication February 8, AlphaMed Press /2007/$30.00/0 doi: /theoncologist The Oncologist 2007;12:

Stanway, Delavault, Purohit et al. 371 INTRODUCTION Breast cancer continues to be a major cause of death in European and American women, occurring most frequently in postmenopausal women.

2 Stanway, Delavault, Purohit et al. 371 INTRODUCTION Breast cancer continues to be a major cause of death in European and American women, occurring most frequently in postmenopausal women. In this group of women, the production of estrogens, which have a crucial role in supporting the development and growth of breast tumors, is greatly reduced following the cessation of ovarian function. However, estrogens continue to be produced at a low level in postmenopausal women, mainly from the peripheral conversion of androstenedione to estrone. This reaction is mediated by the aromatase complex and takes place mainly in adipose tissue but also in normal and malignant breast tissues [1, 2]. In view of the important role that estrogens have in breast cancer, current therapies in postmenopausal women aim to either block its interaction with the estrogen receptor (ER), by use of an antiestrogen such as tamoxifen or an ER downregulator, or inhibit the conversion of androstenedione to estrone with an aromatase inhibitor (e.g., letrozole, anastrozole, exemestane) [3, 4]. Over the last decade, considerable research has been carried out into the synthesis of steroids with estrogenic properties, which has suggested that, in addition to aromatase, another enzyme, steroid sulfatase (STS), may also have a crucial role in regulating the synthesis of estrogenic steroids in breast cancer [5]. Potent STS inhibitors have now been developed, paving the way to use this new type of therapy for breast cancer. STS STS is the enzyme responsible for the hydrolysis of steroid sulfates to their unconjugated, biologically active forms. After the synthesis of estrone from androstenedione by aromatase, much of it is rapidly sulfated to estrone sulfate (E1S) by a number of sulfotransferases that are widely distributed throughout the body [6]. Plasma concentrations of E1S are times higher than those of the unconjugated estrogens, estrone and estradiol [7]. Furthermore, the halflife of E1S in plasma (10 12 hours) is considerably longer than that for estrone and estradiol (20 30 minutes). E1S is therefore thought to act as a reservoir for the formation of active estrogens via the action of STS [8]. This enzyme converts E1S to estrone that is then reduced to the biologically active estrogen, estradiol, by 17 -HSD1, which is overexpressed in many breast tumors (Fig. 1). STS also acts on other steroid sulfates, including dehydroepiandrosterone sulfate (DHEAS), which is secreted in large amounts (up to 20 mg per day) by the adrenal cortex [9]. STS converts DHEAS to DHEA, which can be reduced to androstenediol by 17 -HSD1. Androstenediol, although an androgen, can bind to the ER and stimulate the growth of Figure 1. Pathways of steroidogenesis in postmenopausal women and site of action of STX64 (BN83495). Abbreviations: DHEA, dehydroepiandrosterone; DHEAS, dehydroepiandrosterone sulfate. hormone-dependent breast cancer cells in vitro and carcinogen-induced mammary tumors in rodents [10, 11]. Although its affinity for the ER is lower than that of estradiol, it has been suggested that, because of its much higher plasma and tissue concentrations, it may be equipotent to estradiol in postmenopausal women [12]. STS IN BREAST TUMORS Research carried out some years ago initially revealed that STS activity was detectable in most breast tumors examined. STS activity was found to be present at a considerably higher level than aromatase and aromatase activity was only detectable in about 60% of tumors [13, 14]. Recently STS mrna expression has been measured in breast tumors and shown to be at a much higher level than aromatase mrna expression [15]. Such studies also revealed that STS mrna expression is higher in malignant than in normal breast tissue. Several studies have suggested that high levels of STS mrna expression in breast tumors are associated with a poor prognosis, whereas aromatase or 17 - HSD1 expression had no prognostic value [16, 17]. Thus, with the advent of potent STS inhibitors, the measurement of breast tumor STS mrna expression may allow a patient enrichment strategy to be adopted to target patients who may particularly benefit from this therapy. STS INHIBITORS IN PROSTATE AND ENDOMETRIAL CANCERS Although STS inhibitors were primarily developed for breast cancer therapy, they may also have a therapeutic role

3 372 Steroid Sulfatase in other hormone-dependent cancers, such as those occurring in the prostate and endometrium. STS activity is present in prostatic tissue and in LNCaP cells, which were derived from prostatic cancer tissue [18, 19]. In men with prostate cancer, castration results in only a 50% reduction in prostatic tissue concentrations of dihydrotestosterone [20]. It is thought that the remaining contribution originates from adrenal androgens, such as DHEAS, by an intracrine process within the prostate. Furthermore, therapies that aim to reduce prostatic testosterone concentrations (e.g., luteinizing hormone releasing hormone agonists) do not reduce androstenediol concentrations. This androgen can activate a mutated form of the androgen receptor that is found in LNCaP cells and in many prostatic tumors [21]. Thus, inhibiting STS activity in men with prostate cancer may reduce not only the production of testosterone from DHEAS but also androstenediol. STS activity is increased in endometrial cancer tissue, so its inhibition may also have therapeutic potential, by reducing estrogen synthesis, in this hormone-dependent cancer [22]. STS INHIBITORS Several potent irreversible STS inhibitors have now been identified, all of which have as their active pharmacophore an aryl ring to which a sulfamate ester is attached. The structure of the first-generation STS inhibitor STX64 (BN83495, also known as 667 Coumate) is shown in Figure 2. STX64 was shown to be a potent STS inhibitor in rodents and blocked the ability of E1S to stimulate the growth of carcinogen-induced mammary tumors in ovariectomized rats [23]. Second-generation STS inhibitors, such as the steroid-based STX213 (Fig. 2), have now been developed, which inhibit STS activity in rodents, after the administration of a single dose, for a much longer period of time than STX64 [24, 25]. These STS inhibitors are orally active with a high level of bioavailability. This results from their binding to carbonic anhydrase II in erythrocytes after absorption, which enables them to transit the liver without undergoing first-pass inactivation [26]. CLINICAL USE OF STX64 The first-ever phase I trial of an STS inhibitor in postmenopausal women with locally advanced or metastatic breast cancer was recently reported by our group [27]. All the patients in the trial had been heavily pretreated with endocrine therapies (antiestrogen and/or aromatase inhibitors) while some had also received chemo- or radiotherapy. The primary endpoint of the study was to determine the dose of STX64 that inhibited STS activity by 90% in peripheral blood lymphocytes (PBLs), which have a high level of STS activity. Secondary endpoints included an examination of Figure 2. Molecular structures of STX64 and the secondgeneration steroid sulfatase inhibitor STX213. the ability of the drug to inhibit STS in tumor samples obtained from some patients and its effect on serum androstenediol and estrogen concentrations. The drug was administered orally, with patients receiving an initial dose (cycle 0) followed by 3 2 weekly cycles (cycles 1 3), with each cycle consisting of daily dosing for 5 days followed by 9 days off treatment. Patients in whom disease was stable at the end of cycle 3 were eligible for extended dosing. The drug was well tolerated, with only a few minor adverse events recorded. At a dose of 5 mg, 90% inhibition of STS activity in PBLs was achieved, and at the higher dose tested, 20 mg, almost complete inhibition of STS activity in PBLs and tumor tissue was detected (Fig. 3). Inhibition of STS activity was associated with significant reductions in serum androstenediol and estrogen concentrations. Unexpectedly, serum concentrations of androstenedione, the main substrate for aromatase in postmenopausal women, also decreased by up to 86%. This finding indicates that, in this group of women, androstenedione is derived mainly from the peripheral conversion of DHEAS and not, as previously thought, by direct secretion from the adrenal cortex. Of eight patients who completed cycles 0 3 of treatment, five showed evidence of stable disease for up to 7.0 months (range months) by the Response Evaluation Criteria in Solid Tumors. Importantly, all of the patients showing evidence of stable disease had previously been treated with, and progressed on, aromatase inhibitor therapy. The therapy was well tolerated, although all patients experienced some taste disturbance that was thought to be related to the formulation of the drug. SUMMARY Research into the pathophysiological role of STS in breast cancer led to the development of potent STS inhibitors, one of which has now been tested in a phase I trial of postmeno-

4 Stanway, Delavault, Purohit et al. 373 Figure 3. Inhibition of steroid sulfatase (STS) activity by STX64 in peripheral blood lymphocytes (PBLs) and tumor tissue, at 5-mg and 20-mg doses, in postmenopausal women with metastatic breast cancer. Median values for STS activity ( quartile range) are shown pre- and post-treatment. Comparison of STS activity before and after treatment was carried out using the Wilcoxon signed rank test (PBL STS, pre- versus posttreatment p.002; tumor STS p.016). Figures in parentheses represent the percentage of inhibition achieved. Adapted from Stanway SJ, Purohit A, Woo LWL et al. Phase I study of STX 64 (667 Coumate) in breast cancer patients: The first study of a steroid sulfatase inhibitor. Clin Cancer Res 2006;12: pausal women with metastatic breast cancer. Results from that trial showed that STX64 almost completely blocked STS activity in PBLs and tumor tissues. Inhibition of STS activity was associated with significant decreases in not only serum concentrations of estrogens but also that of androstenediol, a steroid with potent estrogenic properties. Production of androstenediol is not blocked by aromatase inhibitors. Interestingly, this study also revealed that the main aromatase substrate in postmenopausal women, androstenedione, is derived mainly from DHEAS, rather than through direct secretion from the adrenal cortex. Although all patients had been pretreated with endocrine agents, and in some cases chemotherapy, five of the eight patients who completed cycles 0 3 of their treatment showed evidence of stable disease. These encouraging results will be followed by further trials in women with breast cancer to define the optimal biological dosing schedule. A patient enrichment strategy will also be employed taking advantage of measurements of STS mrna expression in tumors to select patients most likely to benefit from this new type of therapy. It will be particularly important to confirm that STS inhibitors can offer therapeutic benefit in patients who have progressed on antiestrogen and/or aromatase inhibitor therapies. It is anticipated that inhibition of STS activity will give rise to a significant clinical benefit and a favorable risk/benefit ratio in the setting of locally advanced or metastatic disease by offering a potential new additional option of endocrine therapy, initially in patients whose disease has progressed after prior aromatase inhibitor therapy. As this drug effectively blocks the production of androgens in addition to estrogens, it is also likely to be tested in other hormone-dependent tumors, such as prostate and endometrial cancer. ACKNOWLEDGMENTS This research was supported by Sterix, a member of the Ipsen Group. DISCLOSURE OF POTENTIAL CONFLICTS OF INTEREST P.D. and C.T. own stock in Ipsen. M.J.R., B.V.L.P., and A.P. have acted as consultants for and received support from Ipsen. M.J.R. and B.V.L.P. have served on the Board of Sterix. REFERENCES 1 Purohit A, Ghilchik MW, Duncan L et al. Aromatase activity and interleukin-6 production by normal and malignant breast tissues. J Clin Endocrinol Metab 1995;80: Reed MJ, Purohit A. Breast cancer and the role of cytokines in regulating estrogen synthesis: An emerging hypothesis. Endocr Rev 1997;18: Cole MP, Jones CTA, Todd IDH. A new anti-oestrogenic agent in late breast cancer. An early clinical appraisal of ICI Br J Cancer 1971; 25: Smith IE, Dowsett M. Aromatase inhibitors in breast cancer. N Engl J Med 2003;348: Reed MJ, Purohit A, Woo LWL et al. Steroid sulfatase: Molecular biology, regulation, and inhibition. Endocr Rev 2005;26: Hobkirk R. Steroid sulfation. Trends Endocrinol Metab 1993;4: Ruder HJ, Loriaux L, Lipsett MB. Estrone sulfate: Production rate and metabolism in man. J Clin Invest 1972;51: Reed MJ, Purohit A, Woo LWL et al. The development of steroid sulfatase inhibitors. Endocr Relat Cancer 1996;3: Purohit A, Dauvois S, Parker MG et al. The hydrolysis of oestrone sulphate and dehydroepiandrosterone sulphate by human steroid sulphatase expressed in transfected COS-1 cells. J Steroid Biochem Mol Biol 1994;50: Poulin R, Labrie F. Stimulation of cell proliferation and estrogenic response by adrenal C19-delta 5-steroids in ZR-75 1 human breast cancer cell line. Cancer Res 1986;46: Dauvois S, Labrie F. Androstenedione and androst-5-ene-3,17 -diol

5 374 Steroid Sulfatase stimulate DMBA-induced rat mammary tumors role of aromatase. Breast Cancer Res Treat 1989;13: Spinola PG, Marchetti B, Labrie F. Adrenal steroids stimulate growth and progesterone receptor levels in rat uterus and DMBA-induced mammary tumors. Breast Cancer Res Treat 1986;8: James VHT, McNeill JM, Lai LC et al. Aromatase activity in normal breast and breast tumor tissue: In vivo and in vitro studies. Steroids 1987;50: Tilson-Mallett N, Santner SJ, Feil PD et al. Biological significance of aromatase activity in human breast tumors. J Clin Endocrinol Metab 1983;57: Utsumi T, Yoshimura N, Takeuchi S et al. Elevated steroid sulfatase expression in breast cancers. J Steroid Biochem Mol Biol 2000;73: Utsumi T, Yoshimura N, Takeuchi S et al. Steroid sulfatase expression is an independent predictor of recurrence in human breast cancer. Cancer Res 1999;59: Miyoshi Y, Ando A, Hasegawa S et al. High expression of steroid sulfatase mrna predicts poor prognosis in patients with estrogen receptor-positive breast cancer. Clin Cancer Res 2003;9: Farnsworth WE. Human prostatic dehydroepiandrosterone sulfate sulfatase. Steroids 1973;21: Selcer KW, Kabler H, Sarap J et al. Inhibition of steryl sulfatase activity in LNCaP human prostate cancer cells. Steroids 2002;67: Titus MA, Schell MJ, Lih FB et al. Testosterone and dihydrotestesterone tissue levels in recurrent prostate cancer. Clin Cancer Res 2005;11: Mizokami A, Koh E, Fujita H et al. The adrenal androgen androstenediol is present in prostate tissue after androgen deprivation therapy and activates mutated androgen receptor. Cancer Res 2004;64: Yamamoto T, Kitawaki J, Urabe M et al. Estrogen productivity of endometrium and endometrial cancer tissue; influence of aromatase on proliferation of endometrial cancer cells. J Steroid Biochem Mol Biol 1993;44: Purohit A, Woo LWL, Potter BVL et al. In vivo inhibition of estrone sulfatase activity and growth of nitrosomethylurea-induced mammary tumors by 667 COUMATE. Cancer Res 2000;60: Fischer DS, Chander SK, Woo LWL et al. Novel D-ring modified steroid derivatives as potent, non-estrogenic steroid sulfatase inhibitors with in vivo activity. J Steroid Biochem Mol Biol 2003;84: Foster PA, Newman SP, Chander SK et al. In vivo efficacy of STX213, a second-generation steroid sulfatase inhibitor, for hormone-dependent breast cancer therapy. Clin Cancer Res 2006;12: Ho YT, Purohit A, Vicker N et al. Inhibition of carbonic anhydrase II by steroidal and non-steroidal sulphamates. Biochem Biophys Res Commun 2003;305: Stanway SJ, Purohit A, Woo LWL et al. Phase I study of STX 64 (667 Coumate) in breast cancer patients: The first study of a steroid sulfatase inhibitor. Clin Cancer Res 2006;12:

Effect of Tamoxifen or Anastrozole on Steroid Sulfatase Activity and Serum Androgen Concentrations in Postmenopausal Women with Breast Cancer

Effect of Tamoxifen or Anastrozole on Steroid Sulfatase Activity and Serum Androgen Concentrations in Postmenopausal Women with Breast Cancer S.J. STANWAY 1, C. PALMIERI 2, F.Z. STANCZYK 3, E.J. FOLKERD